Effects of cerebellar rTMS on cognitive function in Alzheimer’s disease: a randomized controlled fNIRS trial

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a research focus in the treatment of Alzheimer’s disease (AD). However, the optimal stimulation target remains controversial and requires urgent resolution. To evaluate the cognitive effects of 5 Hz rTMS targeting the cerebellar Crus II region in patients with AD and to explore the underlying neural mechanisms using functional near-infrared spectroscopy (fNIRS). A total of 35 patients with AD diagnosed at the mild cognitive impairment or mild dementia stage based on cerebrospinal fluid biomarkers were initially enrolled and randomly assigned to a real rTMS group ( n = 18) or a sham stimulation group ( n = 17), with 33 patients (17 and 16, respectively) completing the full intervention and being included in the final analysis. All patients received two weeks of bilateral 5 Hz rTMS or sham stimulation over the cerebellar Crus II region. Neuropsychological assessments were performed at baseline, immediately post-treatment, and at week 12. Resting-state fNIRS data were collected at baseline and post-treatment. Between-group differences in cognitive scores, cerebral functional activity, and brain network topology after intervention were analyzed. Compared with the sham group, the real rTMS group showed significant improvement in global cognition post-treatment, and this effect persisted until week 12. fNIRS analysis revealed that after treatment, the real rTMS group exhibited significantly increased fractional amplitude of low-frequency fluctuations (fALFF) in the left frontal pole and left dorsolateral prefrontal cortex (DLPFC), along with enhanced functional connectivity across the cerebral cortex. Graph theory analysis showed significant increases in global efficiency, local efficiency, and clustering coefficient, and significant decreases in characteristic path length and normalized characteristic path length in the real rTMS group post-treatment. Correlation analysis indicated that the increase in fALFF in the DLPFC was positively correlated with improvements in MMSE and Digit Span Test scores, while improvement in delayed recall score of the Auditory Verbal Learning Test was correlated with decreased normalized characteristic path length. Five Hz rTMS applied to the cerebellar Crus II region effectively improves cognitive function in patients with mild AD, with benefits persisting for at least three months. fNIRS-based mechanistic analyses suggest that the therapeutic effects may involve cerebellar-cortical loop modulation of hemodynamic activity in key frontal regions, accompanied by enhanced whole-brain functional connectivity and optimized network topology. However, given that fNIRS measures hemodynamic responses rather than direct neuronal activity, these findings should be interpreted as network-level hemodynamic changes rather than as direct evidence of neuronal reorganization. The study was registered at chictr.org.cn website (ID: ChiCTR2200061754) on 02–07-2022.